Dataset Information

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

ABSTRACT:

Importance

Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored.

Objective

To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons.

Design, setting, and participants

Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies.

Main outcomes and measures

The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss.

Results

Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies.

Conclusions and relevance

In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

SUBMITTER: Shulman JM

PROVIDER: S-EPMC4039209 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Shulman Joshua M JM Yu Lei L Buchman Aron S AS Evans Denis A DA Schneider Julie A JA Bennett David A DA De Jager Philip L PL

JAMA neurology 20140401 4

<h4>Importance</h4>Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored.<h4>Objective</h4>To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons.<h4>Design, setting, and participants</h4>Eighteen candidate single-nu ...[more]

PMID: 24514572

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Project description:Co-existing neuropathological comorbidities have been repeatedly reported to be extremely common in subjects dying with dementia due to Alzheimer disease. As these are likely to be additive to cognitive impairment, and may not be affected by molecularly-specific AD therapeutics, they may cause significant inter-individual response heterogeneity amongst subjects in AD clinical trials. Furthermore, while originally noted for the oldest old, recent reports have now documented high neuropathological comorbidity prevalences in younger old AD subjects, who are more likely to be included in clinical trials. Comorbid neuropathologies in subjects with Parkinson disease have received much less attention. As with AD, comorbidities may interfere with the evaluation of PD clinical trials. We have here examined the decadal-wise presence of multiple co-pathologies, and their clinical effects, in a series of autopsies of PD and control subjects from the Arizona Study of Aging and Neurodegenerative Disorders. Amyloid plaques were present in more than 40% of PD patients in their 60s, and in 85% of those in their 90s. Neurofibrillary tangles were present in PD, as in all elderly humans, from the 60s onwards, while Braak tangle stages of IV or greater, which are strongly associated with severe cognitive impairment, reached 40%, 50% and 60% in those subjects in their 70s, 80s and 90s, respectively. Both plaques and tangles were significant predictors of a lower MMSE score while greater CAA scores had borderline significance. None of these, however, were independently associated with a higher UPDRS score. The ApoE4 allele, while a known predictor of AD pathology, especially amyloid plaques, was not an independent predictor of function with either of these clinical measures, suggesting that its influence is largely mediated by the neuropathologies that it predisposes to. Non-AD tauopathies, including the major conditions of progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as the microscopic changes of argyrophilic grains (ARG) and aging-related tau astrogliopathy (ARTAG), also co-existed with PD, especially ARG and ARTAG, which ranged between 20% and 40% across decades for the former and up to 80% for the latter; we did not find significant associations of either with final MMSE or UPDRS scores. We failed to find a significant association of limbic TDP-43 histopathology with either final MMSE score or final UPDRS motor score but our subjects were more heavily weighted with PD than those in prior studies and our cognitive correlate, limited to MMSE score, may have missed associations with cognitive domain subsets. We found several cerebrovascular pathologies to be predictors of both cognitive and motor impairment, including brain infarcts, circle of Willis atherosclerosis, and higher white matter rarefaction score. All of the investigated pathology types were common in the non-demented, non-parkinsonian control subjects, and all increased with age in parallel with those co-existing with PD, while with generally lower prevalences. The high concurrence rate of the neurodegenerative protein aggregate diseases is suggestive of either a synergistic co-pathogenesis, where one aggregate type may instigate or accelerate another type, or of one or more underlying predisposing physiological or molecular mechanisms.

Dataset Information

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Publications

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Similar Datasets

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